Efficacy and prognostic factors of COVID‐19 vaccine in patients with hepatocellular carcinoma: Analysis of data from a prospective cohort study

Abstract Background The efficacy of coronavirus disease 2019 (COVID‐19) vaccines in preventing SARS‐CoV‐2 infection in patients with hepatocellular carcinoma (HCC) is not clear. Methods From January 2022 to October 2022, patients diagnosed with HCC in a prospective, multicenter, observational cohort were analyzed. Results One hundred and forty‐one patients with (n = 107) or without COVID‐19 vaccination (n = 34) were included. The number of patients with severe or very severe infection was relatively lower in the vaccinated group (3.7% vs. 11.8%, p = 0.096). Median infection‐free survival in the vaccinated group (14.0 vs. 8.3 months, p = 0.010) was significantly longer than that in the unvaccinated group. COVID‐19 vaccination (hazard ratio (HR) HR = 0.47), European Cooperative Oncology Group performance score = 0 (HR = 2.06), and extrahepatic spread (HR = 0.28) were found to be the independent predictive factors for infection‐free survival. Conclusion COVID‐19 vaccines could effectively reduce the SARS‐Cov‐2 infection in patients with HCC.


| INTRODUCTION
Hepatocellular carcinoma (HCC) represents approximately 85% of primary liver cancer, and it is unique because it usually occurs in patients with underlying chronic liver diseases, which may cause a number of abnormalities, including abnormal blood tests, impaired immunological reactions, or even death from complications of chronic liver diseases. 1,2In comparison to healthy adults, patients with HCC were noted to have higher mortality after the SARS-CoV-2 infection. 3Moreover, in patients with chronic liver disease, HCC was shown to be an independent risk factor for higher mortality associated with SARS-CoV-2 infection. 4n studies of patients with HCC, the safety of the coronavirus disease 2019 (COVID-19) vaccine was found to be acceptable.However, the immunogenicity of the COVID-19 vaccine was found to be lower than that of other patients or healthy adults. 5,6Given the paucity of definitive evidence, the efficacy of administering COVID-19 vaccines to this population remains a topic of debate.This study aims to investigate the efficacy and prognostic factors of COVID-19 vaccines for preventing SARS-CoV-2 infection in patients with HCC, to inform future strategies for the prevention and management of global infectious diseases.

| Study design
The prospective, multicenter, observational Primary Liver CanCer cohort (PLCC cohort), which was approved by the ethics committee of Cancer hospital, Chinese Academy of Medical Sciences, and registered in Chinese Clinical Trial Registry (identifier: ChiCTR2200056326), enrolled all consecutive patients, who were diagnosed with primary liver cancer, had no history of local or systemic treatments and voluntarily consented to participate in the cohort since January 2022.The PLCC cohort aims to prospectively observe and record the general characteristics (e.g., vocation, social support, laboratory parameters, radiological and pathological features) and the health behaviors (e.g., nutritional status, exercise, COVID-19 vaccination status) in patients with primary liver cancer, and further investigate the relationship between the factors and their prognosis.Informed consents were collected from all patients.From January 2022 to October 2022, all patients (≥18 years old) diagnosed with HCC in the PLCC cohort were considered to be eligible for the analyses.Patients with other pathological types of primary liver cancer were excluded.To evaluate the efficacy of vaccines in preventing SARS-CoV-2 infection, patients who had a history of SARS-CoV-2 infection before enrollment were excluded.
To investigate the relationship between the COVID-19 vaccination and overall survival, a certain period of followup (e.g., 12 months) was necessary.In addition, the most significant outbreak of COVID-19 in mainland China occurred at the end of 2022. 7Prior to this, the infection rate was merely 0.7‰, as a result of the dynamic zero-COVID policy in mainland China. 8Therefore, October 2022 was decided as the deadline for enrollment in this study.

| Data collection and follow-up
Baseline clinical, laboratory, radiological, and COVID-19-related data (e.g., vaccination status, type of vaccine, vaccine-related adverse reactions) were prospectively collected immediately after enrollment.Subsequent followup visits were scheduled at 6-week intervals to collect information regarding SARS-CoV-2 infection, adverse reactions, survival, and other pertinent data.Vaccinerelated adverse reaction was defined as adverse reactions occurring within seven days of the injection, which were related to the COVID-19 vaccination. 9The relationship between the adverse reactions and vaccination was determined by the investigators.Infection-free survival was defined as the time from enrollment to the SARS-CoV-2 infection.Overall survival was defined as the time from enrollment to death from any cause.

| Patient recruitment
A total of 165 patients were screened during the study period.None of the patients had a history of SARS-CoV-2 infection.Patients with intrahepatic cholangiocarcinoma (n = 10), combined hepatocellular-cholangiocarcinoma (n = 7), hepatic sarcoma (n = 2), neuroendocrine neoplasm (n = 2), sarcomatoid carcinoma (n = 2), and cancer of unknown primary origin (n = 1) were excluded.No patient had a history of SARS-CoV-2 infection before enrollment.Finally, a total of 141 patients with HCC (85.5%) were included in the analyses (Figure S1).One hundred and seven patients (75.9%) who received at least one dose of the COVID-19 vaccine were categorized into the vaccinated group, and the other 34 (24.1%)patients were categorized into the unvaccinated group.

| DISCUSSION
Previous studies have shown that the safety and immunogenicity of the COVID-19 vaccine are acceptable in patients with HCC. 10,11However, the efficacy and prognostic factors of COVID-19 vaccines in patients with HCC remain unclear.In the current study, we found that in patients with HCC, (1) COVID-19 vaccines could effectively decrease the occurrence of SARS-CoV-2 infection; (2) COVID-19 vaccination, ECOG performance status ≥1, and extrahepatic spread were the independent protective factors for the SARS-CoV-2 infection; and (3) SARS-CoV-2 infection, portal invasion, and maximum tumor diameter >5 cm were the independent risk factors for overall survival.There is a 53% lower risk of SARS-CoV-2 infection in patients with COVID-19 vaccination, a 72% lower risk of SARS-CoV-2 infection in patients with extrahepatic spread, and a 2.06 times higher risk of SARS-CoV-2 infection in patients with ECOG performance status = 0. We suspected that the inability and restrictions in social contacts could be the major reasons for the lower infection rate in HCC patients with poor performance status.Nevertheless, this hypothesis requires further substantiation.There is a 68% lower risk of mortality in patients with SARS-CoV-2 infection, and 75% lower risk of mortality in patients with a maximum tumor diameter ≤5 cm, and a 2.51 times higher risk of death in patients with portal invasion.In addition, the occurrence of severe SARS-CoV-2 infection was nearly three times less common in vaccinated patients, which suggests that the COVID-19 vaccines may also help to reduce the severity of SARS-CoV-2 infection.3][14] There are some limitations to this study.First, the sample size is relatively small (n = 141).Second, the majority of patients (99.3%) in the current study received inactivated COVID-19 vaccines.Consequently, further studies focusing on the efficacy of the COVID-19 mRNA or viral vectored vaccines are warranted in the future.Third, patients with prior SARS-CoV-2 infection were not included in this study.In this population, Kaur et al. conducted several excellent studies and found that the COVID-19 vaccines could modestly reduce the SARS-CoV-2 infection. 13,15,16Fourthly, the vaccine-related adverse reactions were not classified into short-term or long-term adverse reactions.Kaur et al. found a higher risk of long-term adverse events after receiving COVID-19 vaccines in patients with a history of SARS-CoV-2 infection. 15,16Therefore, further studies focusing on patients with prior SARS-CoV-2 infection and the long-term adverse reactions are warranted.At last, as the median overall survival was not reached, the findings about overall survival should be interpreted with caution.In conclusion, the COVID-19 vaccines could effectively reduce the SARS-CoV-2 infection in patients with HCC.

F I G U R E 1
SARS-CoV-2 infectionfree survival and overall survival in patients with hepatocellular carcinoma.(A) SARS-CoV-2 infection-free survival; (B) Overall survival.
Univariate and multivariate analyses for SARS-CoV-2 infection-free survival.
T A B L E 1Note: Candidate variables with a p < 0.20 on univariate analysis were included in multivariable analysis.Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer staging system; ECOG, European Cooperative Oncology Group; HBV, hepatitis B virus; HR, hazard ratio.a COVID-19 vaccination represents the number of patients who received at least one dose of COVID-19 vaccine.